NIH Study Topples Conventional View of Opioid Mechanism of Action

A new discovery shows that opioids, like morphine and oxycodone, have their effect by binding to receptors inside neurons, whereas previous understanding was that they acted on the surface receptors. Researchers funded by the National Institute on Drug Abuse (NIDA), turned to a molecular probe to challenge the previous understanding. They discovered that medically used opioids also bind to receptors that aren’t the target for naturally occurring opioids

This difference between how medically used and naturally made opioids interact with nerve cells may help guide the design of pain relievers that do not produce addiction or other adverse effects that can occur with other opioid medicines.

“This ground-breaking study has uncovered important distinctions between the opioids that our brain makes naturally and therapeutic opioids that can be misused,” said NIDA Director Nora D. Volkow, M.D. “This information can be mined to better understand the potential adverse actions of medically prescribed opioids and how to manipulate the endogenous system to achieve optimal therapeutic results without the unhealthy side effects of tolerance, dependence, or addiction.”

Naturally occurring opioids and medically used opioids alike bind to the mu-opioid receptor, a member of a widespread family of proteins known as G protein-coupled receptors (GPCRs). Recent advances in understanding the three-dimensional structure of GPCRs have enabled researchers to create a new type of antibody biosensor, called a nanobody, that generates a fluorescent signal when a GPCR is activated. This enables scientists to track chemicals as they move through cells and respond to stimuli.

Using this nanobody, the researchers first showed that when a naturally occurring opioid binds to and activates the mu-receptor on the surface of a neuron, receptor molecules enter the cell inside what is known as an endosome. There, the mu-receptor remains activated over a period of several minutes, which itself was a new discovery, since it was believed that the opioid receptor is only activated on the surface of nerve cells. Proteins that interact with receptors on the cell surface control all sorts of biological processes and provide targets for therapeutic intervention.

With opioid medications, however, the researchers made two additional discoveries. First, there are large differences across a range of clinically relevant opioid drugs in how strongly they induce receptor activation in endosomes. Second, the opioid drugs uniquely induce rapid nanobody signaling, within tens of seconds, in an internal cellular structure known as the Golgi apparatus in the main body of the neuron. Further investigation showed that therapeutic opioids also uniquely activate mu-opioid receptors in related structures, known as Golgi outposts, in the long, branched structures of neurons.

Based on these findings, the researchers hypothesize that current medically used opioids distort the normal time and spatial sequence of mu-opioid receptor activation and signaling. This distortion may provide the mechanistic link that explains the undesired side effects of opioid medicines suggests new avenues for designing agents that do not produce addiction or other adverse effects associated with these drugs.

“This new biosensor opens our eyes to a previously unknown level of diversity and specificity in the cellular actions of opioids,” said Dr. Miriam Stoeber, the study’s first author. Dr. Mark von Zastrow, senior author of the study, added, “We were surprised to see that drugs such as morphine activate opioid receptors in a location at which naturally occurring opioids do not.”

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It doesnt matter if the “new opiods”are available tomorrow, because nobody will be able to afford them. Hopefully more people realize that the pharm company needs to make a minimum profit margin of between 4000 and 5000% othrtwise they wont be able to afford THEIR meds…lol I am truley disgusted with the level of greed in this country. The values my mom brought me up with simply are impossible to uphold in the current “way of the world”. SORRY MOM…everything is F****d up so bad anyway.

5 months ago

HOWARD HEROLD

IVE ALSO BEEN ON OPIOIDS FOR OVER 23 YEARS, THEY ARE TAKEN CORRECTLY AND NOT FOR A HIGH !!!! THATS WHAT DOCTORS HAVE IN THEIR MINDS, OH, HE JUST WANTS TO GET HIGH !!!! TOTAL B.S. !!!!!! WE, ARE SICK OF IT.

7 months ago

Hayden

Ignorance is evidently bliss. I wish that I was an “expert” so I could con my way into resources($$$$$$$). Unfortunately I am just a 23 year patient with irreversible pain that have gained the same amount of years of mobility amd ability with a tailored dosge of opioid medications WITHOUT diverting OR abusing my medication but, that makes no difference. WE as patients don’t need “new”medication that will be unaffordable, just take a simple glance at our years and decades of positive use, beneficial use, successful use. of what we have used for decades but, change brings lined pockets (money) to the so called “experts”.

8 months ago

Missy

Besides the fact this article is basically gibberish to me here’s what I think. I don’t believe a word coming out of anyone’s mouth (anyone with power). I don’t believe “scientists, drug companies, committees, and my top two offenders, government (either party) and politicians (either party)! So many people have their hands in the marijuana business (nothing against pot) that I see corruption everywhere!! California (aka.. pot capital) has filed multiple lawsuits against drug manufacturers who make OxyContin and blaming THEM for the “made up” so called opioid crisis!! I mean it’s perfect…sue the companies we so badly need for our chronic pain medicines, while making millions and hoping for billions in marijuana sales! If you can’t get your opioid
prescriptions, California wants to be welcoming you with open arms into their pot stores!! What a racquet AND at our expense! Now, full disclosure, I am a RA/fibromyalgia patient who has successfully been taking opioids for over 15 years. The great thing about opioids is you can take them with little to no side effects at all. I could work, cook, travel, yes drive, walk, garden etc… but without the daily intake of these medicines I could quickly be in misery, unable to get off the couch, more fatigued, stressed etc.. pain from my diseases are constant, always there and only put at ease with opioids. Now, I’m taking, Cymbalta, Lyrica, muscle relaxers, steroids and half the opioids I
use to take. Also regular facet injection surgeries are part of my “new must haves” by doctors. I feel worse pain, groggy, gained twice my weight, have brain zaps and am always fatigued & sleepy. Having done both regiments I was happiest, in my best health and most productive with my opioid meds only. Adding all the other “treatments” has taken me backwards with far worse results! And they say opioids are bad we’ve got to change these medicines!! Give me a break! They do work and whatever this mumbo jumbo their talking about doing to opioid medications is nuts!! And for all you out there in love with pot I think that’s great but most of us will continue
living in states with no
access to medicinal
marijuana. Meanwhile
I’m having so much [edit]
shoved down my throat causing every unkind side effect while at the
same time supposedly
smart people are
saying,”ohhh noooo
opioids are bad for
incurable diseases, here take these 14 other pills”! 🙄
I say leave pain medicines alone! Enough damage is done already!

The pity is that our Government scientists have known since 1987 the “the opioids that our brain makes naturally” are morphine and it’s precursors. Yet the Government’s top experts, who now teach at SUNY Neuroscience in Westbury, Long Island, are never visited by New York City reporters who try to cover the “Opioid Crisis”.

What are news editors afraid to learn?

Why won’t they interview the opioid experts, to learn about opioids?

Is it possible, that if chronic pain results from a morphine shortage, then our entire thinking about what addiction is, is false?

Might it be that inflicting more suffering on addicts to force them to “hit bottom”, simply does not work?

8 months ago

B. Gould

You know I think if everybody needs a reality check there is no hundred percent cure for pain there is no medication out there that you can take on an ongoing basis that won’t have some side effects. Look at all the lawsuits going on in the medical industry from medication that has been on the market for short and long term years. You know we jumped the gun on so much and it hurts so many. Opiate has helped greatly whether people want to admit it or not. And unfortunately you have to take the good with the bad the good here is that people are able to live a more Humane life and to be able to participate and function more. It is the only thing that is really helped chronic pain patients and we’re trying to take it away and we’re trying to put something else in a place that we’re not sure of yet. The government and rehab facilities are quick to want to get anything on the market but we haven’t done any testing and that thinking alone is dangerous. Here’s the thing because of illegal drug use and people trying to put a label on opiates they have made opiates a dirty word. So now when anybody speaks about opiates they’re not speaking of the good it’s doing their speaking of it as an addiction and assuming that patients are using it as an high when in reality patients are using it as a means of survival to help them function to help them get out of bed. Patients that are properly managed through the medical process are taking opiates not to get high on the medication. They take it because it is designed to be effective for their severity of their conditions. Maybe we just need to change the name associated with the pain medicine given to patients with chronic pain issues because then maybe the interpretation will change for the public. We need to put something else in front of the public to concentrate on and that’s heroin smack and other street drugs. That’s what the campaign should be so we can take the focus off of The Chronic pain patients so they can live their lifes which already are more of a challenge then most will ever be able to comprehend.

8 months ago

Heather

Maybe it’s that I’m feeling that our current situation is a tidal wave and that we’re being pushed along helplessly as chronic pain patients…

…but we kind of needed this type of research before things came to a crisis level with this “opioid epidemic” (that I feel heroin and street-available fentanynl seems to be the real issues).

Drug companies need to scramble now, but what could they have been doing all along? They ought to stop and ask themselves what role they had in ignoring “non-essential” lines of research that would have benefited patients and maybe have kept them from being in a position where states are suing them.

They need to think about more than profit. Honestly. They also need to be more realistic and transparent about how much they spend on marketing, how much they’re spending on drug safety… They’re claiming development costs for drugs that were developed by the government (like Epi-pens). They really need to win back public trust and to do that, they need to take major steps to be more responsible. But it isn’t going to happen because it seems they saw what happened to Martin Shkreli and thought it was just because he was an attention-craving, arrogant slimeball.

It wasn’t just who he was or that he was so arrogant. It was a wake-up call to other companies that their time is coming. Everything is going to be on display and the public is going to start asking the right questions and pressuring the politicians whose pockets are being lined. Public pressure will win this one.

8 months ago

Dane Sullivan

I’d like to know why I have to lie in bed every day with cages in my back I snapped in half bone in my arm after for Ella replacements and a 17-year-old daughter and have no life because I can’t get my painkillers and I don’t even have Medicare for my prescriptions I have private prescriptions am I supposed to just die like this?